Polycyclic hydrocarbons are ubiquitous in the urban environment and many are carcinogenic. The proximal carcinogen, however, is considered to be an epoxide which is formed during the metabolic transformation of the polycyclic hydrocarbons. The objective of this reserach proposal is to investigate the enzyme responsible for the formation of the epoxides (arylhydrocarbon hydroxylase) in the organs likely to be exposed to polycyclic hydrocarbons (lung, intestine, liver). More specifically, it is intended to study the manner in which other environmental contaminants (insecticide synergists) and intentionally administered drugs (sympathomimetics) can affect this reaction and so alter the carcinogenic potential of the polycyclic hydrocarbon. The reason for selecting these two groups of compounds is that both the methylenedioxyphenyl insecticide synergists (e.g., piperonyl butoxide) and sympathomimetic amines (e.g., amphetamine) have, upon metabolism, been shown to interact with cytochrome P-450 to produce complexes having absorption maxima at 455 nm. The complex formed upon piperonyl butoxide metabolism has been shown to be a potent noncompetitive inhibitor of hepatic cytochrome P-450 dependent reactions. It is intended to determine whether this inhibition applies to arylhydrocarbon hydroxylase in organs other than liver and whether similar complexes from sympathomimetic amines also inhibit these reactions. Also, it is intended to determine whether the reported enzyme-inducing properties of piperonyl butoxide are related to the formation of the complex, and subsequently, whether the sympathomimetic amines also cause induction. With this knowledge we will be able to better assess and so control the carcinogenic potential of polycyclic hydrocarbons in the environment. BIBLIOGRAPHIC REFERENCES: Buening, M. K., and Franklin, M. R. (1975) "The formation of cytochrome P-450-455nm complexes during amine metabolism in rabbit liver, lung, and small intestine," in Fed. Proc., 34, 729. Franklin, M. R. (1975) "The relationship between the cytochrome P-450-455nm complex from amphetamines and the dual ethylisocyanide absorbance maxima," in Pharmacologist 17, 185.